J P H Wilding Endocrine testing in obesity 182:4 C13–C15

Commentary

Endocrine testing in obesity

Correspondence
should be addressed
John P H Wilding
to J P H Wilding
Obesity and Endocrinology Research, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK Email
J.P.H.Wilding@liverpool.ac.uk

Abstract
Endocrine disorders such as Cushing’s syndrome and hypothyroidism may cause weight gain and exacerbate
metabolic dysfunction in obesity. Other forms of endocrine dysfunction, particularly gonadal dysfunction
(predominantly testosterone deficiency in men and polycystic ovarian syndrome in women), and abnormalities of
the hypothalamic-pituitary-adrenal axis, the growth hormone-IGF-1 system and vitamin D deficiency are common in
obesity. As a result, endocrinologists may be referred people with obesity for endocrine testing and asked to consider
treatment with various hormones. A recent systematic review and associated guidance from the European Society of
Endocrinology provide a useful evidence summary and clear guidelines on endocrine testing and treatment in people
with obesity. With the exception of screening for hypothyroidism, most endocrine testing is not recommended in the
absence of clinical features of endocrine syndromes in obesity, and likewise hormone treatment is rarely needed.
European Journal of Endocrinology

These guidelines should help reduce unnecessary endocrine testing in those referred for assessment of obesity and
encourage clinicians to support patients with their attempts at weight loss, which if successful has a good chance of
correcting any endocrine dysfunction.

European Journal of
Endocrinology
(2020) 182, C13–C15

Obesity is a common and important disease with many
adverse health consequences (1). Endocrinologists see
many people with obesity, either because of clinical
suspicion of an underlying endocrine cause for weight
gain or because of concern that obesity may have caused
endocrine dysfunction. This bidirectional relationship
between obesity and endocrine dysfunction is complex,
and the ESE has provided both a systematic review
looking at the associations between obesity and common
endocrine disorders (2) and practical guidance about
appropriate investigations and treatment (3).
Key areas investigated in the systematic review were
the prevalence of thyroid disorders (overt hypothyroidism,
subclinical hypothyroidism and hyperthyroidism) in
obesity, hypercortisolism and gonadal dysfunction
– low testosterone in men and PCOS in women. It is
important to highlight that most of the studies were not
population-based, but clinical samples of people seeking
treatment for obesity, including several studies of people
considering or undergoing bariatric surgery, and did not
include comparator populations of people without obesity
investigated using similar methodology. Although the
researchers have followed guidance for such systematic
reviews and assessed risk of bias, the wide range of
prevalence reported for all of the conditions studied clearly
highlights the uncertainty around these estimates and
highlights some important areas for future clinical research.
Thyroid disease
For hypothyroidism the reported prevalence (combining
diagnosed and undiagnosed hypothyroidism) varied from
1.7 to 47% with a mean of 14% across studies. Subclinical
hypothyroidism was equally common. These results seem
higher than the reported prevalence of these conditions
in unselected populations in Europe (4, 5). This may
reflect the age and gender of the studied populations
(older with a greater proportion of females), rather
than a genuinely higher rate in obesity. Nevertheless,
the recommendation to screen for thyroid dysfunction
in obesity seems pragmatic, given the high prevalence

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 Commentary J P H Wilding
and relatively straightforward treatment. However, the
authors are correct to recognise that thyroid dysfunction
is rarely a cause for obesity and highlight that, in most
people, the increase in weight with hypothyroidism is
modest (a few kg) and usually reversible with thyroxine
treatment. For those with subclinical hypothyroidism
(elevated TSH with normal free T4), thyroxine treatment
is not recommended as a means to encourage weight loss.
Glucocorticoid excess
Compared with thyroid disease, glucocorticoid excess
is rare and other clinical features are often present. It is
important to note that some of the studies included in the
systematic review only included patients with additional
features such as hypertension, diabetes or other symptoms
and signs of glucocorticoid excess, so it is likely that
these studies are of populations somewhat enriched for
the likelihood of Cushing’s syndrome. Most used simple
European Journal of Endocrinology
screening tests (either an overnight dexamethasone
suppression test, salivary or urinary cortisol) followed
by further investigation if these were suggestive of
glucocorticoid excess. All the studies were small and only
identified a few cases of Cushing’s syndrome. Overall, the
prevalence was 0.9%, which seems high compared to the
general population (6), and again may reflect that these
were clinical populations, none were population-based
studies and some found no cases of glucocorticoid excess.
The interpretation of screening tests for glucocorticoid
excess in obesity is difficult because obesity and associated
conditions such as depression may result in subtle
abnormalities in the hypothalamic-pituitary-adrenal axis.
Nevertheless, secondary screening investigations such as
with a high dose dexamethasone suppression test would
usually identify such patients, and it was done in most of
the reported studies; it thus seems likely that most of the
reported cases reflect true glucocorticoid excess, although
in some the workup seemed inconclusive. The conclusion
to offer screening tests in the presence of clinical features
seems reasonable given the relatively low prevalence in
largely unselected populations.
Hypogonadism in males
There is no question that male hypogonadism is associated
with an increase in body fat that may contribute to
metabolic abnormalities, such as dyslipidaemia and
dysglycaemia. Obesity may itself result in dysfunction
of the hypothalamic-pituitary-gonadal axis and thus
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Endocrine testing in obesity 182:4 C14
contribute to hypogonadism in men. In the meta-analysis,
the prevalence of male hypogonadism in obesity was 37%
and was higher in those with more severe obesity, such as
in patients seeking bariatric surgery, which is consistent
with the known biology. Most men with obesity-associated
hypogonadism will be asymptomatic, although non-
specific features such as fatigue are common. Those with
specific symptoms such as erectile dysfunction, infertility
and other clinical features are more likely to have significant
hypogonadism, and in these people, investigation is
deemed appropriate. Assessment of gonadal function is
not always straightforward, and full clinical evaluation
is recommended in those with symptoms, including
examination of testicular size as well as appropriate
biochemical testing either of free testosterone or total
testosterone (in fasted early morning samples) plus SHBG
along with measurement of gonadotrophins.
Weight loss may restore gonadal function and is
recommended as the first line of treatment unless other
pathology is present; however, a trial of testosterone
replacement can be considered in the presence of
symptoms and confirmed biochemical hypogonadism,
with the usual caveats about avoiding use in those
with prostate cancer, with PSA screening, prior and
during treatment. Monitoring full blood count is also
recommended to check for an increased haematocrit.
Gonadal dysfunction in females –
polycystic ovary syndrome
Polycystic ovary syndrome (PCOS) is common, affecting
between 9 and 25% of women with obesity, according
to the systematic review, but it is also similarly prevalent
in the absence of obesity (7). Screening for PCOS is not
advised in obesity, unless women have symptoms such as
menstrual disturbance, infertility or hirsutism.
The guidelines advise that weight loss should be the
first line approach for women with obesity and PCOS.
Metformin is recommended in the guidelines for those with
metabolic syndrome, although the evidence supporting its
use is relatively weak, and it is not currently licensed for use
in women with PCOS. There is some evidence of benefit
in women with PCOS who also have glucose intolerance,
and this is the only group in whom it is recommended by
NICE in the United Kingdom. The risks and benefits of
metformin should be made clear to patients and potential
adverse effects, including gastrointestinal symptoms and
vitamin B12 deficiency discussed if it is to be prescribed.
Metformin is also not recommended during pregnancy,
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 Commentary J P H Wilding
which is an important consideration, as many women with
PCOS will present with infertility.
Growth hormone and IGF1
Growth hormone (GH) deficiency contributes to an
increase in body fat and a decrease in muscle mass. It is
also associated with metabolic abnormities, including an
atherogenic lipid profile and glucose intolerance. Growth
hormone secretion may be impaired in severe obesity;
however, there is little evidence that this results in lower
IGF-1 concentrations or contributes to the metabolic
abnormalities. The guidelines correctly conclude that GH
and IGF-1 testing is not necessary in people with severe
obesity and that GH treatment is not indicated unless
there is clear evidence of GH deficiency.
Vitamin D and parathyroid hormone
European Journal of Endocrinology
Vitamin D deficiency is common in Northern European
populations and low vitamin D concentrations are
prevalent in obesity. The guidelines do not support
routine testing for vitamin D or PTH testing, except
in those undergoing bariatric surgery, as there is little
evidence to support the idea that vitamin D replacement
will favourably alter metabolic status or body weight,
even in those who are clinically deficient.
Measurement of other hormones: leptin
and ghrelin
Circulating concentrations of the adipose tissue hormone
leptin are usually increased in obesity; the exception being
rare cases of leptin deficiency that would be expected to
present at a very young age with severe obesity. Routine
testing of leptin is therefore unnecessary. The gut hormone
ghrelin is a powerful stimulus to appetite, but there is no
evidence that excess ghrelin is a cause of obesity, although
raised ghrelin may contribute to increased appetite in
Prader–Willi syndrome. Measurement of ghrelin or other
gut hormones that influence appetite such as GLP-1 is not
helpful in the management of people with obesity.
In conclusion, people with obesity and many referring
clinicians often seek reassurance from endocrinologists
Endocrine testing in obesity 182:4 C15
that an underlying hormonal imbalance is the cause
of their weight gain and associated symptoms. In most
people, simple reassurance is all that is required, but
some (encouraged by inaccurate information available
online and elsewhere) can request repeated and complex
investigations to exclude endocrine disease or the use of
hormones in the mistaken belief that these will help them
lose weight. These new guidelines from the ESE should
be welcomed, as they provide clear recommendations
about screening for endocrine conditions in people with
obesity and a rational approach to further investigation
and treatment when endocrine conditions are suspected
or diagnosed.
Declaration of interest
The author has acted as a consultant for and received lecture fees from Novo
Nordisk, Rhythm pharmaceuticals and Orexigen who produce treatments
for obesity. None of these treatments are discussed in this article.
Funding
This research did not receive any specific grant from any funding agency in
the public, commercial or not-for-profit sector.
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Received 5 February 2020
Revised version received 12 February 2020
Accepted 18 February 2020
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